1. Field of the Invention
The present invention relates generally to the field of radiation therapy. More specifically, the present invention relates to a method for treatment of toxicity due to radiation therapy.
2. Description of the Related Art
Radiation therapy is an important strategy in the treatment of many cancers. The use of external beam radiation therapy has produced curative treatment programs for several tumor types. However, this technique has practical limitations in regards to the field of therapy, radioresistance mechanisms, and normal tissue toxicity. The risk of chronic intestinal toxicity (radiation enteropathy) is the main dose-limiting factor during abdominal radiation therapy and is a major determinant in the quality of life in cancer survivors.
Inflammatory and fibrogenic mediators released by mucosal inflammatory cells are involved in the mechanisms of toxicity. The pathophysiological mechanisms of the toxicity may include mucosal barrier break-down, extracellular matrix deposition or intraluminal factors. Chronic enteropathy may be due to endothelial dysfunction, chronic inflammation, or an oxidative imbalance. Attempts to prevent radiation enteropathy by reducing the dose to volume ratio include abdominopelvic partitioning or patient positioning such as using a belly-board. To date, treatment for radiation enteropathy is limited to pharmacologic-dietary intervention methods to try to interfere with or modulate the normal tissue response.
In the clinical situation, radiation therapy is usually not administered as a single dose, but as multiple daily fractions, primarily because the dose-response curve with fractionated radiation is less steep than for single dose radiation. Also, fractionated radiation is associated with what can be regarded as a xe2x80x9cfractionated immune responsexe2x80x9d. For these reasons, radioprotectors that show protection with single dose radiation sometimes do not show significant protection when tested with fractionated radiation.
Thus, the prior art is deficient in preventing radiation enteropathy following radiation treatments for cancer, and in treating the disorder once it occurs. This deficiency has resulted in limited doses of radiation therapy administered to cancer patients. The present invention fulfills this long-standing need and desire in the art.
The present invention describes the use of orazipone for ameliorating intestinal radiation toxicity. Results presented herein suggest that administration of orazipone prior to, during and after small bowel irradiation effectively reduces radiation-induced histopathologic injury, inflammation, and TGF-xcex2 overexpression.
Previous attempts at identifying radioprotective agents for clinical use have been largely hampered by a) toxicity, b) issues of possible tumor protection, and/or c) unfavorable price/efficacy ratio. Strategies to ameliorate radiation enteropathy have been under investigation for some time. One approach has been to interfere with the mechanism of injury by eliminating reactive oxygen species, inhibiting apoptosis, and/or stimulating DNA repair. Another approach has been to interfere with the normal tissue response to try to abrogate tissue injury and/or increase tolerance.
The advantages of the drug, orazipone, are that it is active locally and is administered directly into the intestine. The small amounts that are absorbed are rapidly broken down to inactive metabolites. Toxicity at effective dose levels is thus minimal, and tumor protection is not an issue (with the possible exception of intestinal tumors).
One object of the present invention is to provide a method for the prevention and/or treatment of radiation enteropathy.
One embodiment of the present invention provides a drug to be administered locally to ameliorate radiation toxicity, such as, enteropathy in a patient in need of such treatment.
In yet another embodiment of the present invention, there is provided a drug to be administered locally for a period of time prior to, during and following therapeutic radiation which decreases and/or prevents the radiation toxicity in a patient suffering from cancer.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure.